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1 With main focus on the Estrogen Receptor Commentary The best way to achieve optimal treatment of today s patients is to ensure the availability of reliableand timelypathological th l i l assessment in routine practice including treatment target identification Anne-Vibeke Lænkholm Department of Pathology Næstved-Slagelse Denmark Three questions in the evaluation of biomarkers Question Feature Is it true? Analytical Validity Is it meaningful? Clinical Validity Is it useful? Clinical Utility Analytic Validity of a biomarker refers to its accuracy in measuring what it is supposed to measure sensitivity and specificity of the assay Assay robustness Clinical Validity Refers to the predictive value of a biomarker for a given clinical outcome ie ER Clinical Utility Is the biomarker helpful in improving or maintaining the health of patients Treatment strategy Luminal A: ER-positive, HER2-negative, Ki67- low and Luminal B: ER-positive, HER2-negative, Ki67> 14% or LuminalB: ER-positive, HER2-overexpressed or amplified, any Ki67 HER2-positive (non luminal): HER2 overexpressed or amplified and ER negative Triple-negative: ER-negative, (PR-negative), HER2-negative 1

2 Risk of recurrence pr. year N = 3,562 patients Lin, N. U. et al. J Clin Oncol; 26: Copyright American Society of Clinical Oncology Positive in app. 8 (ER) of breast carcinomas cut off 1% 1-9% low 1 high PR Unknown (%) Negative ( %) positive (%) TOTAL ER Unknown (%) 54 (0.71) 1 (0.01) 2 (0.03) 57 (0.75) ER-pos./PR-pos. ER-pos./PR-neg. ER-neg./PR-pos. ER-neg./PR-neg. Serving as control for false negative ER? Negative (%) 55 (0.72) 1269 (16.65) 23 (0.3) 1347 (17.67) Positive (%) 547 (7.18) 1154 (15.14) 4518 (59.27) 6219 (81.58) TOTAL 656 (8.61) 2424 (31.80) 4543 (59.60) 7623 (100) Risk Factors and Risk Groups Danish Breast Cancer Cooperative Group (DBCG) Age Tumor size Lymph node status 60 years < 60 years 10 mm negative I: IDC I + II: ILC Grade ER % HER2 Risk Groups I (low) II (high) II +III: IDC III: ILC 1 negative I Positive i II 0-9% II 1 II positive > 10 mm II Christiansen P et al. J Natl Cancer Inst Sep 21;103(18): II II 6% (2012) Preanalytical standardization Fixation 1 NBF within 1 hour Fixation time: 6 (at least) 72(nomore than) hours. Analytical standardization Antibody/Antigen Retrieval/Detection Systems Control samples Postanalytical standardization Interpretation Cut-off level Internal quality control Tissue / Material Image Analysis? Participation in quality assurance programs 2

3 Antibody ERα SP1 monoclonal rabbit (12) (Thermocycler or Ventana) Clone 6F11 Monoclonal mouse (1) (Novocastra) Dilution Ready To Use (majority) 1:100 Detection system Optiview-DAB Ultraview-DAB EnVision EnVision Flex+ Rabbit The majority of the pathology laboratories in Denmark apply the Benchmark Ultra (Ventana Medical Systems) for ER staining. A few laboratories apply the Dako autostainer (DAKO /Denmark) All Danish Breast Cancer Cooperative Group (DBCG) unknown biopsi Lump 1-9% Mast Danish Breast Cancer Cooperative Group Change of cut-off from 1 to 1% biopsi unknown Lump 1-9% Mast Scoring method Algoritm type Definitions Range of scores Allred score PS + IS PS: 0:none; 1: <1%; 2: 1-1; 3: 10-33% ; 4: 33-66%; 5: >66% IS: 0: none; 1: weak; 2: moderate; 3:strong H-score Sum of (PS at a given ISxIS) Semiquantitative Bright Field LM IHC4 (ER, PR, KI67, HER2) IHC subtype Mathematical model PS: 1-10; IS: o: none; 1: weak; 2: moderate; 3:strong Percentage positive tumor cells Cut-off value 1 Creation of an IHC4 score Variation of IHC4 0, Determination of ER: Biochemical method, ex. dextran coated charcoal (DCC) and presently immunohistochemistry Cut-off value 1% (range 1-10) Poor dynamic range Thorpe et al. Eur J Cancer % mesured ER positive by DCC (age<70), median value of ER is 42 fmol/mg cytosol protein (0-2542) IHC: No method to determine the exact amount of protein by weight in IHC exists. The influence of fixation and HIER on protein loss is largely unknown, hence estimation of staining intensity can be unreliable. Shi et al. J Histochem Cytochem 2011;59:

4 Is the prevalence of ER (IHC) expression in primary breast cancer dependent on the choice of antibody and HIER? Guideline recommendations Arch Pathol Lab Med 2010;134:48-72 Only methods with pre-analytical and analytical components conformed exactly to clinically validated assays or compared with the clinically validated assays should be used for prediction of response for endocrine treatment Positive agreement must be 9 Negative agreement 95% Positive results are defined as 1% immuno-reactive cells Cheang MC et al. J Clin Oncol 2006; 24: The proportion of ER positive breast cancers increased from 63% to 71% when SP1 was used instead of 1D5 with superior prognostic information. Higher antibody affinity causes increased ER positivity in other organs i.e. lung adenocarcinomas. Lau SK et al. Appl Immunohistochem Mol Morphol 2006;14: D5, SP1 n= patients 500 TMA Evaluable TMA 1D5, SP1 PharmDx n=321 PharmDx n=361 Tissue Micro Array (TMA) Results agreement 1D5 SP1 1D5 Cut-off 1% - + SP Overall agreement (95+263)/ (89-94) Negative agreement 95/ (68-84) Positive agreement 263/ (97-99) Cut-off SP Overall agreement ( )/ (91-96) Negative agreement 109/ (74-88) Positive agreement 257/ (99-100) Guideline Positive agreement must be 9 Negative agreement 95% Positive results are defined as 1% immunoreactive cells compared with a clinically validated assay 1D5 and SP1 b 1.00 Recurrence-free survival, cut-off 1%, +TAM e 1.00 Recurrence-free survival, cut-off 1, +TAM vs : p=0.37 vs : p= Years vs : p=0.07 vs : p= Number at risk Number at risk Years In conclusion: The proportion of ER postive breast cancer increased from 68% to 75% (cut-off 1%) when SP1 was used compared to 1D5. The choice of antibody and HIER influences the prevalence of ER-positivity. When applying changes in the staining procedure caution must be taken towards the guideline recommendations concerning positive and negative agreement with clinically validated assays Core Needle Biopsy 4

5 Slide courtesy of Eva Balslev Östrogen receptor Surgical tumor specimens Core Needle Biopsies (CNB) Tissue Micro Array (TMA) Small biopsies from metastastic sites i.e. bone (decalcified tissue) NordiQC : Positive staining reaction of the stromal cells indicates that a high sensitive protocol is being applied. ER CNB < 1% CNB 1-10 SS <1% 8 1 SS No Neoadjuvant Chemotherapy N=89, bimodal distribution Concordance 98% Ranked correlation 1 (rho) Sensitivity Specificity 1 Conclusion: With a cutoff value 1%, ER on CNB is sufficiently accurate and reliable. Histological malignancy grade, estrogen receptor and HER2 receptor status on core needle biopsy compared to surgical specimen in breast cancer how accurate is it? Munch-Petersen HD, Balslev E. APMIS: Special Issue: Abstracts of the Annual Meeting of the Danish Pathology Society, March 2013, Randers, Denmark March 2013, Volume 121, Issue Supplement s135, Page 8 In case of negative ER on Core Needle Biopsy repeat analysis on surgical specimen 5

6 Discrepancy of results A change of 8-33% in Hormone Receptor status was reported PR more discordant than ER Retesting of Hormone Receptor is recommended Bernsdorf M et al. Breast Cancer Res Treat 2011 Jul;128(1): Value of postoperative reassessment of estrogen receptor α expression following neoadjuvant chemotherapy with or without gefitinib for estrogen receptor negative breast cancer. Study Henriksen KL et al. J Clin Pathol 2007;60: Rossing HH et al. APMIS 2012; ; 120: Thomas A et al. Am J Clin Pathol 2009;132: Sapino A et al. Virchows Arch 2006;449: Number of cases ER Size (mm) and number of cores Scoring Method 54 2 x 2 Allred score x 2 categorized groups (10) x 4 4 methods including intensity and number of positive tumor cells x 1 Quick score/allred >98 Recommended publication: Pinder SE et al. The manufacture and assessment of tissue microarrays: suggestions and criteria for analysis, with breast cancer as an example. J Clin Pathol 2013; 66: (On behalf of the Translational Subgroup of the NRCI Breast Clinical Studies Group) Concordance (%) 97.7 (Ventana Ab) 99.2 (Dako Ab) ER discrepancy: 12 29%, often with loss of receptor HER2 discrepancy: 6 2, often with gain of HER2+ Limitations: Many pathology chart review studies, did not reanalyse tumor samples (methodological variation) Prospective studies: -Biopsy had treatment consequence in Benign disease/other malignancies in 14% Standardization of staining methodology Preanalytical Analytical Postanalytical According to American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations (Arch Pathol Lab Med. 2010;134:e48-e72) Staining protocols have to be adjusted to the tissue material of interest When applying changes in the staining procedure caution must be taken towards the guideline recommendations concerning positive and negative agreement with clinically validated assays Application of controls on all ER, (PR) stained slides Repeat staining on surgical specimen (whole section) in case of ER negative result on primary Core Needle Biopsy or TMA. Repeat staining on surgical specimens after neoadjuvant chemotherapy in any case of ER staining. Attendance in external Quality Assurance Programs Routine ER, PR, HER2 and KI67 used in combination as binary categories are not the same as a (centrally dertermined) IHC score (based on continuous variables) or multivariate genomic predictors. Dr. Lajos Pusztai, St. Gallen Slide courtesy of Jeanette Dupont Jensen. Department of Oncology, Odense University Hospital, Denmark Departments of Pathology, Denmark Giedrius Lelkaitis Aalborg University Hospital Tomasz Piotr Tabor Holstebro Hospital Morten Johansen Vendsyssel Hospital Henrik Mertz Randers Hospital Gorm Søndergaard Viborg Hospital Vibeke Jensen Aarhus University Hospital Tina Di Catarino Sydvestjysk Hospital, Esbjerg Birthe Østergaard Vejle Hospital Thomas Poulsen Sønderjylland Hospital, Sønderborg Anne-Marie Bak Jylling Odense University Hospital Henrik Mygind Slagelse Hospital Maj-Lis Møller Talman Copenhagen University Hospital Eva Balslev and Birgitte Bruun Rasmussen Herlev Hospital Danish Breast Cancer Cooperative Group (DBCG) Karsten Bjerre Susanne Møller Maj-Britt Jensen ER receptor status in Core Needle Biopsy. How accurate is it? Helga Duverger Munch-Petersen & Eva Balslev Department of Pathology, Herlev Hospital, Denmark The prevalence of ER positivity Dorthe Grabau Department of Pathology, Skåne University Hospital, Lund, Sweden. Pär-Ola Bendahl and Mårten Fernö Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden Lisa Rydén Department of Surgery, Skåne University Hospital, Lund, Sweden. Olle Stål Department of Clinical and Experimental Medicine, Division of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden Acta oncologica 2013; PMID: Jeanette Dupont Jensen Department of Oncology, Odense University Hospital, Odense, Denmark 6

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